Ikervis^® (Drops) Instructions for Use

Marketing Authorization Holder

Santen, Oy (Finland)

Manufactured By

Excelvision (France)

Quality Control Release

SANTEN, OY (Finland)

Contact Information

SANTEN LLC (Russia)

ATC Code

S01XA18 (Ciclosporin)

Active Substance

Ciclosporin (Rec.INN registered by WHO)

Dosage Form

Ikervis®

Eye drops 1 mg/1 ml: dropper tubes 0.3 ml 30 pcs.

Dosage Form, Packaging, and Composition

Eye drops in the form of a milky-white emulsion.

Excipients: medium-chain triglycerides, tyloxapol, cetalkonium chloride, glycerol, poloxamer 188, 0.1M sodium hydroxide solution (for pH adjustment), water for injections.

0.3 ml – single-use polyethylene dropper tubes^× (5) – sealed sachets made of laminated aluminum foil (6) – cardboard cartons.

^× connected in 1 strip of 5 dropper tubes.

Clinical-Pharmacological Group

Immunosuppressant for topical use in dry eye syndrome

Pharmacotherapeutic Group

Other ophthalmologicals

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Ciclosporin (also known as Ciclosporin A) is a cyclic polypeptide immunomodulator with immunosuppressive properties.

It has been shown to prolong the survival of allogeneic grafts in animals and significantly improves graft survival in all types of solid organ transplantation in humans.

It has also been demonstrated that Ciclosporin has an anti-inflammatory effect.

Results from animal studies have confirmed that Ciclosporin inhibits the development of cell-mediated reactions.

It has been noted that Ciclosporin inhibits the production and/or release of pro-inflammatory cytokines, including interleukin 2 (IL-2) or T-cell growth factor (TCGF).

It is also known to activate the release of anti-inflammatory cytokines.

Ciclosporin appears to block inactive lymphocytes in the G₀ or G₁ phase of the cell cycle.

All available data indicate that Ciclosporin acts specifically and reversibly on lymphocytes, does not suppress hematopoiesis, and does not have any effect on the function of phagocytic cells.

In patients with dry eye syndrome associated with an immune-inflammatory mechanism, after instillation into the eyes, Ciclosporin is passively absorbed into T-lymphocyte infiltrates in the cornea and conjunctiva of the eye and inactivates calcineurin phosphatase.

Ciclosporin-induced inactivation of calcineurin inhibits the dephosphorylation of the nuclear factor of activated T-cells (NF-AT) transcription factor and prevents the translocation of NF-AT into the nucleus, thus blocking the release of pro-inflammatory cytokines such as IL-2.

Clinical efficacy and safety

The efficacy and safety of Ikervis^® were evaluated in two double-blind, placebo-controlled, randomized clinical studies involving adult patients with dry eye syndrome (dry eye disease) who met the criteria of the International Dry Eye Workshop (DEWS).

In a 12-month, double-blind, placebo-controlled core clinical study (SANSIKA study), 246 patients with dry eye syndrome (DED) accompanied by severe keratitis [the severity of which was determined by corneal fluorescein staining (CFS) with a score of 4 on the modified Oxford scale] were randomly assigned to study groups where they received either one drop per day of Ikervis^® or placebo at bedtime for 6 months.

Patients randomized to the placebo group were switched to Ikervis^® after 6 months.

The primary efficacy endpoint was defined as the percentage of patients who achieved at least a two-point improvement in keratitis (CFS) and a 30% improvement in symptoms assessed by the Ocular Surface Disease Index (OSDI) by month 6 of therapy.

The percentage of patients who responded to treatment in the Ikervis^® group was 28.6%, compared to 23.1% in the placebo group.

The difference was not statistically significant (p=0.326).

The severity of keratitis, assessed by CFS, significantly decreased at 6 months compared to baseline with the use of Ikervis^® compared to placebo (mean change from baseline was -1.764 in the Ikervis^® group and -1.418 in the placebo group, p=0.037).

The percentage of patients treated with Ikervis^® who showed a 3-point improvement in CFS scores at 6 months (from 4 to 1) was 28.8% compared to 9.6% in the placebo group; however, this analysis was retrospective, which limits the robustness of the significance assessment of the outcome.

The beneficial effect on keratitis persisted in the open-label phase of the study from month 6 to month 12.

The mean change from baseline in the 100-point OSDI scale was -13.6 in the Ikervis^® group and -14.1 in the placebo group at 6 months (p=0.858).

Furthermore, there were no improvements in other secondary endpoints in the Ikervis^® group compared to the placebo group at 6 months, including eye discomfort score, Schirmer’s test results, concomitant use of “artificial tear” preparations, investigator’s global assessment of efficacy, tear film breakup time, lissamine green staining, quality of life score, and tear fluid osmolarity.

A reduction in inflammatory changes on the ocular surface, assessed based on the expression of human leukocyte antigen DR (HLA-DR) (an exploratory endpoint), was predominant at 6 months in the Ikervis^® group (p=0.021).

In a 6-month double-blind, placebo-controlled clinical study (SICCANOVE), 492 patients with dry eye syndrome accompanied by moderate or severe keratitis (characterized by a CFS score of 2-4) were also randomized to the Ikervis^® and placebo groups, followed by administration of the study drug at bedtime for 6 months.

The composite primary efficacy endpoints were the change in CFS scores and the change in overall eye discomfort score unrelated to the study drug at 6 months.

A small but statistically significant difference in CFS improvement was observed between the study groups at month 6 in favor of Ikervis^® (mean change in CFS scores from baseline was -1.05 in the Ikervis^® group and -0.82 in the placebo group, p=0.009).

The mean change in eye discomfort (assessed using a Visual Analog Scale) from baseline was -12.82 in the Ikervis^® group and -11.21 in the placebo group at 6 months (p=0.808).

In both studies, no benefits were observed with Ikervis^® compared to placebo at 6 months of treatment, either using the Visual Analog Scale (VAS) or OSDI.

In both studies, on average, one third of the patients suffered from Sjögren’s syndrome; in the general population, a statistically significant improvement in CFS was noted with the use of Ikervis^®, as well as a significant reduction in symptom severity.

After completing participation in the SANSIKA study (12-month study), patients were offered to transition to the Post SANSIKA study.

This was an open-label, non-randomized, 24-month extension study to the SANSIKA study involving a single group of patients.

In the Post SANSIKA study, patients received Ikervis^® or no treatment depending on CFS scores (patients received Ikervis^® when keratitis worsened).

The aim of the study was to monitor the long-term efficacy and relapse rate in patients previously treated with Ikervis^®.

The primary objective of the study was to assess the duration of improvement after discontinuation of Ikervis^® from the time this improvement was achieved compared to baseline in the SANSIKA study (i.e., at least a 2-point improvement on the modified Oxford scale).

The study included 67 patients (37.9% of the 177 patients who completed the SANSIKA study).

At 24 months, 61.3% of the 62 patients included in the primary efficacy population had no relapse according to the CFS scale.

The percentage of patients who experienced a severe relapse of keratitis was 35% and 48% among those who received Ikervis^® in the SANSIKA study for 12 months and 6 months, respectively.

Based on the first quartile (the median could not be assessed due to the small number of relapses), the duration of the period until relapse (to CFS grade 4) was ≤244 days and ≤175 days in patients who received Ikervis^® for 12 months and 6 months, respectively.

Patients spent more time with CFS grade 2 (median 12.7 weeks/year) and grade 1 (median 6.6 weeks/year) than with CFS grade 3 (median 2.4 weeks/year) and CFS grades 4 and 5 (median 0 weeks/year).

Assessment of DED symptoms using VAS showed an increase in discomfort in patients from the time of first treatment discontinuation until treatment resumption, except for pain, which remained relatively mild and stable.

The median VAS score overall increased from the time of first treatment discontinuation (23.3%) to the time of treatment resumption (45.1%).

No significant changes were observed regarding other secondary endpoints (TBUT, lissamine green staining and Schirmer’s test, NEI-VFQ and EQ-5D) during the extension study.

Preclinical safety data

Preclinical studies, including radiation studies on pharmacological safety, repeated dose toxicity, phototoxicity and photoallergy, genotoxicity, carcinogenic risk, toxicity to reproductive function and fetal development, have not revealed any hazards to humans.

In preclinical studies, effects of the drug were observed only with its systemic administration or in cases where the degree of drug exposure significantly exceeded the maximum possible exposure in humans, indicating low relevance of these data for clinical use.

Pharmacokinetics

No formal pharmacokinetic studies have been conducted on the use of Ikervis^® in humans.

The concentration of Ikervis^® in the blood was measured using a specific high-performance liquid chromatography-mass spectrometry assay.

In 374 patients in two efficacy studies, cyclosporine plasma concentrations were measured before drug administration and after 6 months of treatment (SICCANOVE and SANSIKA studies), as well as after 12 months of treatment (SANSIKA study).

After using Ikervis^® once daily for 6 months, this indicator was below the lower limit of detection (0.050 ng/ml) in 327 patients, and below the lower limit of quantification (0.100 ng/ml) in 35 patients.

Measurable values not exceeding 0.206 ng/ml were detected in eight patients, which can be considered negligible.

Three patients had values exceeding the upper limit of quantification (5 ng/ml), but they were already taking Ciclosporin orally at a constant dose, which was allowed by the study protocol.

After 12 months of treatment, values were below the detection limit in 56 patients and below the lower limit of quantification in 19 patients.

Measurable values ranging from 0.105 to 1.27 ng/ml were detected in seven patients, which were considered negligible.

Two patients had values exceeding the upper limit of quantification, but they were also taking Ciclosporin orally at a constant dose since enrollment in the study.

Indications

• Treatment of severe keratitis in adult patients with dry eye syndrome in case of ineffectiveness of therapy with artificial tear preparations (see section “Pharmacological action”).

ICD codes

Dosage Regimen

Treatment should be prescribed by an ophthalmologist or a medical specialist qualified in ophthalmology.

The recommended dose is 1 drop into the affected eye(s) once daily at bedtime.

The duration of therapy with Ikervis^® depends on the severity of the disease symptoms and the tolerability of the therapy.

The maximum duration of therapy with Ikervis^® according to clinical observations is about 24 months.

The effectiveness of treatment should be assessed at least every 6 months.

If a dose is missed, treatment should be continued the next day as usual.

Patients should be advised not to instill more than one drop into the affected eye(s).

Special patient groups

Elderly patients

The use of the drug in elderly patients was studied in clinical trials.

Dose adjustment is not required.

Patients with impaired renal or hepatic function

The effect of cyclosporine has not been studied in patients with impaired renal or hepatic function.

Nevertheless, no special measures are required in these patient groups.

Children

There is insufficient experience with the use of cyclosporine for the treatment of severe keratitis in children and adolescents with dry eye syndrome under the age of 18 years in the absence of improvement with artificial tear preparations.

Method of administration

Topically, as instillations into the conjunctival sac.

Precautions before using the drug

Patients should be instructed to wash their hands thoroughly before starting to use the drug.

Before use, the single-use dropper tube should be shaken gently.

For single use only.

The contents of one dropper tube are sufficient for instillation into both eyes.

Any unused emulsion should be disposed of immediately.

Patients should be instructed to use nasolacrimal occlusion and close their eyelids for 2 minutes after instillation to reduce systemic absorption.

This helps to reduce systemic side effects and increase the local activity of the drug.

When using more than one topical ophthalmic drug, they should be applied at 15-minute intervals.

Ikervis^® should be applied last (see section “Special Instructions”).

Instructions for medical use of the drug

Wash your hands.

If the patient wears contact lenses, they must be removed before applying the drops at bedtime.

Insert the lenses after waking up.

Open the aluminum sachet, which contains 5 single-use dropper tubes.

Remove one single-use dropper tube from the aluminum sachet.

Shake the dropper tube gently before use.

Unscrew the cap (Figure 1).

Figure 1

Pull down the lower eyelid (Figure 2).

Figure 2

Tilt your head back and look at the ceiling.

Gently squeeze one drop of the drug into the eye.

Do not touch the eye with the tip of the dropper tube.

Blink several times to distribute the drug over the entire eye.

After applying Ikervis^®, gently press your finger on the corner of the eye near the nose and close your eyelids for 2 minutes (Figure 3).

This will help prevent Ikervis^® from entering the systemic circulation.

Figure 3

If the patient uses the drug in both eyes, repeat all the steps for the other eye.

Dispose of the dropper tube immediately after use, even if there is still some liquid left in it.

The remaining single-use dropper tubes should be stored in the original packaging.

If the drop does not get into the eye, repeat the steps again.

Adverse Reactions

Summary of the safety profile

Among the adverse reactions (ARs), the most frequently reported were eye pain (19.2%), eye irritation (17.8%), lacrimation increased (6.4%), eye hyperemia (5.5%), as well as eyelid erythema (1.7%), which were usually transient and occurred during instillation of the drug.

These ARs are consistent with reactions reported during post-marketing use.

Tabulated summary of adverse reactions

The following ARs listed below were observed in clinical studies or during post-marketing use.

They are ordered according to the system-organ classification and systematized according to the following convention: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

Description of selected adverse reactions

Eye pain

Pain at the instillation site was a frequent local adverse reaction associated with the use of Ikervis^® during clinical trials.

It is likely related to the use of cyclosporine.

Generalized and Local Infections

Patients receiving immunosuppressive therapy, including Ciclosporin, are at increased risk of infections. Both generalized and local infections may develop. Existing infections may also be exacerbated (see the “Contraindications” section). Nevertheless, cases of infections associated with the use of the drug Ikervis^® have been reported rarely.

As a precautionary measure, steps should be taken to reduce systemic absorption (see the “Dosage Regimen” section).

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after registration of a medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions via the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to cyclosporine and/or to any of the excipients included in the drug formulation;
• Ophthalmic or periocular malignant neoplasms or precancerous conditions;
• Active or suspected ocular or periocular infection.

Use in Pregnancy and Lactation

Women of Childbearing Potential/Contraception in Women

The drug Ikervis^® is not recommended for use in women of childbearing potential who are not using effective contraception.

Pregnancy

Data on the use of the drug Ikervis^® in pregnant women are not available.

Animal studies have revealed reproductive toxicity after systemic administration of cyclosporine at doses substantially exceeding the maximum human doses, indicating a virtual absence of reproductive toxicity with the clinical use of the drug Ikervis^®.

The drug Ikervis^® is not recommended for use during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding Period

After oral administration, Ciclosporin passes into breast milk. There is insufficient information on the effect of cyclosporine on newborns/infants. However, at therapeutic doses of cyclosporine in eye drops, it is unlikely that a significant amount will be present in breast milk. A decision should be made either to discontinue breastfeeding or to discontinue therapy with the drug Ikervis^®, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

Data on the effect of the drug Ikervis^® on human reproductive function are not available.

In animals receiving Ciclosporin intravenously, no negative effect on fertility was observed (see the “Preclinical Safety Data” subsection).

Use in Hepatic Impairment

Dose adjustment is not required.

Use in Renal Impairment

Dose adjustment is not required.

Pediatric Use

There is insufficient experience with the use of cyclosporine for the treatment of severe keratitis in children and adolescents with dry eye syndrome under the age of 18 years who have not improved with artificial tear treatment.

Geriatric Use

The use of the drug in elderly patients was studied in clinical trials. Dose adjustment is not required.

Special Precautions

The drug Ikervis^® has not been studied in patients with a history of ophthalmic forms of herpes and should therefore be used with caution in such patients.

Contact Lenses

The use of the drug in patients wearing contact lenses has not been studied. Close monitoring of the condition of patients with severe keratitis is recommended.

Concomitant Therapy

Experience with the use of cyclosporine in patients with glaucoma is limited. When using the drug in the complex therapy of glaucoma, including beta-blockers, which may have a negative effect on tear secretion, regular clinical monitoring of the corneal condition is required.

Effect on the Immune System

Ophthalmic drugs that affect the immune system, which include Ciclosporin, may have adverse effects leading to the development of local infections and the progression of malignancies. In this regard, with long-term use of the drug, regular monitoring of the eye(s) condition is recommended at least once every 6 months.

Excipients

The drug Ikervis^® contains cetalkonium chloride, which may cause eye irritation. With prolonged use, patients should be under observation.

Given the possible effect of cetalkonium chloride on contact lenses, when using the eye drops before bedtime, contact lenses should be removed and put back on after waking up.

Effect on Ability to Drive and Use Machines

The drug Ikervis^® has a moderate influence on the ability to drive and use machines.

This drug may cause temporary blurred vision or other visual disturbances that may affect the ability to drive or use machines (see the “Adverse Reactions” section). Patients should be advised not to drive or use machines until their vision has normalized.

Overdose

Local overdose from instilling the drug into the eye is unlikely. In case of overdose with the drug Ikervis^®, treatment should be symptomatic and supportive.

Drug Interactions

No studies of interaction with other medicinal products have been conducted.

Use in Combination with Other Medicinal Products Affecting the Immune System

Concomitant use of the drug Ikervis^® with eye drops containing corticosteroids may enhance the effect of cyclosporine on the immune system (see the “Special Precautions” section).

Storage Conditions

The drug should be stored in the original packaging (carton) to protect from light at a temperature not exceeding 25°C (77°F). Do not freeze.

Shelf Life

The shelf life is 3 years.

Immediately after use, dispose of the opened single-use container with any remaining amount of emulsion.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.